The low-affinity neurotrophin receptor (p75NTR) can mediate cell survival or cell death by NGF or another neurotrophin stimulation in neuronal cells (1, 2, 3) To elucidate p75NTR-mediated signal transduction, the yeast two-hybrid system was employed to screen the mouse embryo cDNA libraries using the rat p75NTRICD (intracellular domain) as a target. One positive clone was identified and termed NADE (p75NTR-associated cell death executor). This isolated mouse NADE has a significant homology to human HGR74 protein (4) and does not have a typical biochemical motif except the consensus sequences of nuclear export signal (NES) (5) and ubiquitination (6). Expression of NADE mRNA was found highest in the brain, heart, and lung. NADE specifically binds to p75NTRICD both in vitro and in vivo. Co-expression of NADE together with p75NTR dramatically induced Caspase-2 and Caspase-3 activities to clave PARP (poly (ADP-ribose) polymerase) and fragmentation of nuclear DNA in 293T cells, but NADE without p75NTR did not show apoptosis suggesting that NADE expression is necessary for p75NTR mediated apoptosis but is not sufficient to trigger apoptosis. Moreover, NGF dependent recruitment of NADE to p75NTRICD was observed in a dose dependent manner and NADE significantly inhibits NF-kB activation. Interestingly, NADE protein is found to be ubiquitinated as a substrate for protein degradation pathway. Taken together, NADE is the first signal adaptor molecule identified in involvement of p75NTR-mediated apoptosis, and it may play an important role in the pathogenes is of neurogenetic disease.